L Burt Nabors

University of Alabama at Birmingham, Birmingham, AL, United States

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Publications (36)214.82 Total impact

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    ABSTRACT: Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N'G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.
    Journal of Neuro-Oncology 03/2014; · 3.12 Impact Factor
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    ABSTRACT: G207, a mutant herpes simplex virus (HSV) type 1, is safe when inoculated into recurrent malignant glioma. We conducted a phase I trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5Gy radiation dose in patients with recurrent malignant glioma. Nine patients with progressive, recurrent malignant glioma despite standard therapy were included. Patients received one dose of G207 stereotactically inoculated into the multiple sites of the enhancing tumor margin, then treated focally with 5 Gy radiation. Treatment was well tolerated and no patient developed HSV encephalitis. The median interval between initial diagnosis and G207 inoculation was 18 months (mean 23, range, 11-51 months). Six of nine patients had stable disease or partial response for a least one timepoint. Three instances of marked radiographic response to treatment occurred. The median survival time from G207 inoculation until death was 7.5 months (95% CI, 3.0- 12.7). In conclusion, this study showed the safety and the potential for clinical response of single dose oncolytic HSV therapy augmented with radiation in the treatment of malignant glioma patients. Additional studies with oncolytic HSV such as G207 in the treatment of human glioma are recommended.Molecular Therapy (2014); doi:10.1038/mt.2014.22.
    Molecular Therapy 02/2014; · 7.04 Impact Factor
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    ABSTRACT: PURPOSEA randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. PATIENTS AND METHODS Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m(2)); (3) lomustine (110 mg/m(2)) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans.ResultsThe primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. CONCLUSION This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.
    Journal of Clinical Oncology 08/2013; · 18.04 Impact Factor
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    ABSTRACT: Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements of the 3' untranslated region is one mechanism for upregulating these and other growth factors. In glioma cells, we have shown that the post-transcriptional machinery is optimized for growth factor upregulation secondary to overexpression of the mRNA stabilizer, HuR. The negative regulator, tristetraprolin (TTP), on the other hand, may be suppressed because of extensive phosphorylation. Here we test that possibility by analyzing the phenotypic effects of a mutated form of TTP (mt-TTP) in which 8 phosphoserine residues were converted to alanines. We observed a significantly enhanced negative effect on growth factor expression in glioma cells at the post-transcriptional and transcriptional levels. The protein became stabilized and displayed significantly increased antiproliferative effects compared to wild-type TTP. Macroautophagy was induced with both forms of TTP, but inhibition of autophagy did not affect cell viability. We conclude that glioma cells suppress TTP function through phosphorylation of critical serine residues which in turn contributes to growth factor upregulation and tumor progression.
    Journal of Neuro-Oncology 03/2013; · 3.12 Impact Factor
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    ABSTRACT: PURPOSE: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGFR (ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that recurrent glioblastoma patients would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. Methods: A Phase II study evaluated the antitumor activity of pazopanib 400 mg/day plus lapatinib 1000 mg/day in patients with grade IV malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIACs). The Phase II study used a 2-stage Green-Dahlberg design for futility. An independent, parallel Phase I component determined the maximum tolerated regimen (MTR) of pazopanib and lapatinib in grade III/IV glioma patients receiving EIACs. RESULTS: The 6-month progression-free survival rates in Phase II (n=41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting ≥8 weeks. In Phase I (n=34), the MTR was not reached. Based on pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. CONCLUSIONS: The antitumor activity of this combination at the Phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the Phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.
    Clinical Cancer Research 01/2013; · 7.84 Impact Factor
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    ABSTRACT: Background The signal transduction pathways of epidermal growth factor receptor and Ras are both important in the growth of glioblastoma multiforme (GBM). We hypothesized that inhibition of both pathways would improve the survival time of patients with recurrent GBM.Methods Patients with recurrent/progressive GBM with 0-2 prior chemotherapy regimens received erlotinib 150 mg once daily and sorafenib 400 mg twice daily until progression. The primary endpoint was overall survival. Pharmacokinetic sampling was performed during cycle 1.ResultsThe median overall survival was 5.7 months. Progression-free survival at 6 months was 14%. Toxicity was manageable. Clearance of erlotinib was markedly enhanced by sorafenib.Conclusion The study did not meet its objective of a 30% increase in overall survival time compared with historical controls. Erlotinib and sorafenib have significant pharmacokinetic interactions that may negatively impact the efficacy of the combination regimen.
    Neuro-Oncology 01/2013; · 6.18 Impact Factor
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    ABSTRACT: Primary angiosarcoma of the brain is extremely rare; only 15 cases have been reported in adults over the last 25 years. We describe two cases of primary angiosarcoma of the brain that are well characterized by imaging, histopathology, and immunohistochemistry. Case 1: our first patient was a 35-year-old woman who developed exophthalmos. Subtotal resection of a left extra-axial retro-orbital mass was performed. Case 2: our second patient was a 47-year-old man who presented to our facility with acute visual loss, word-finding difficulty and subtle memory loss. A heterogeneously-enhancing left sphenoid wing mass was removed. We also review the literature aiming at developing a rational approach to diagnosis and treatment, given the rarity of this entity. Gross total resection is the standard of care for primary angiosarcoma of the brain. Adjuvant radiation and chemotherapy are playing increasingly recognized roles in the therapy of these rare tumors.
    Journal of Medical Case Reports 08/2012; 6(1):251.
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    ABSTRACT: Hu antigen R (HuR) is an mRNA-binding protein belonging to the ELAV family. It is highly expressed in cancer and involved in cell survival and proliferation. The impact of post-translational regulation of HuR and resulting cellular effects are poorly understood. In the current report, we describe a direct interaction between HuR and Cdk5 in glioma. We determined that Cdk5 specifically phosphorylates HuR at the serine 202 residue in the unique hinge region. The molecular consequences of this interaction are an altered HuR ability to bind, stabilize, and promote translation of mRNAs. At the cellular level, the anomalous HuR phosphorylation at this site evokes robust defects in centrosome duplication and cohesion as well as arrest of cell cycle progression. Subcellular fractionation and immunofluorescence technique confirm a direct integration of HuR and Cdk5 with centrosomes. We propose that HuR stores mRNA in the centrosome and that HuR phosphorylation by Cdk5 controls de novo protein synthesis in near proximity to centrosomes and, thus, impacts centrosome function.
    Journal of Biological Chemistry 07/2012; 287(38):32277-87. · 4.65 Impact Factor
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    ABSTRACT: BACKGROUND: Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. METHODS: In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. RESULTS: Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). CONCLUSIONS: Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose. Cancer 2012. © 2012 American Cancer Society.
    Cancer 04/2012; · 5.20 Impact Factor
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    ABSTRACT: In experimental autoimmune encephalomyelitis (EAE) and other neurodegenerative diseases, astrocytes play an important role in promoting or attenuating the inflammatory response through induction of different cytokines and growth factors. HuR plays a major role in regulating many of these factors by modulating RNA stability and translational efficiency. Here, we engineered transgenic mice to express HuR in astrocytes using the human glial fibrillary acidic protein promoter and found that female transgenic mice had significantly less clinical disability and histopathological changes in the spinal cord. Ovariectomy prior to EAE induction abrogated the protective effect. Our findings support a role for the astrocyte and posttranscriptional regulation in hormonally-mediated attenuation of EAE.
    Journal of neuroimmunology 03/2012; 246(1-2):34-7. · 2.84 Impact Factor
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    09/2011; , ISBN: 978-953-307-646-1
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    ABSTRACT: Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA-binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by short hairpin RNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Because bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV cross-linking and RNA immunoprecipitation, we show that HuR bound to the 3'-untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target.
    Molecular Cancer Research 05/2011; 9(5):648-59. · 4.35 Impact Factor
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    ABSTRACT: Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.
    Future Oncology 03/2011; 7(3):339-54. · 3.20 Impact Factor
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    ABSTRACT: We report two cases of primary CNS lymphoma (PCNSL) treated with high-dose methotrexate. Though standard adult treatment of PCNSL incorporates whole-brain radiotherapy, the literature suggests it may be possible to delay or avoid radiotherapy and the associated increased risk of neurologic sequelae in pediatric patients. Studies in adults indicate methotrexate therapy can be effective against PCNSL and has advantages over the current standard of treatment. Both patients have no evidence of disease 9 and 7 years after treatment, suggesting high-dose methotrexate may lead to disease control in pediatric patients with PCNSL while avoiding the effects of radiotherapy.
    Pediatric Blood & Cancer 09/2010; 55(6):1227-30. · 2.35 Impact Factor
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    ABSTRACT: Previous preclinical studies suggested that concurrent capecitabine and radiation could be an effective new treatment modality for glioblastoma (GBM). In the current study, we investigate toxicity and response to this regimen and explore associations between gene expression and patient outcome. Eighteen newly diagnosed GBM patients received concurrent capecitabine at 625 mg/m2 BID (25% escalation) and irradiation (60 Gy total) for 6 weeks followed by 4 weeks of capecitabine only. Maintenance capecitabine was administered for 14 days every 3 weeks until progression or unacceptable toxicity. Expression analysis of 94 genes involved in capecitabine metabolism and radiation response was done on tissues obtained before therapy. The relationship of gene expression with time-to-progression (TTP) and overall survival (OS) was investigated using univariate Cox proportional hazards regression, semi-supervised principle component analysis, and class prediction modeling. The maximum tolerated dose of capecitabine was 625 mg/m2 BID. Median patient TTP and OS were 247 and 367 days, respectively. Cox regression identified 24 genes significantly (P<0.025) associated with patient outcome. Semi-supervised principle component analysis identified two patient populations significantly different in both TTP (P=0.005) and OS (P=0.015). Class prediction modeling determined that eight genes (RAD54B, MTOR, DCTD, APEX2, TK1, RRM2, SLC29A1, and ERCC6) could collectively classify patients into outcome subgroups with 100% accuracy and precision. Capecitabine and concurrent radiation for newly diagnosed GBM seems to be well tolerated and comparable to temozolomide and radiation. A gene expression profile predictive of patient outcome that may be useful in patient stratification for therapy was also elucidated.
    Clinical Cancer Research 05/2010; 16(10):2890-8. · 7.84 Impact Factor
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    ABSTRACT: Bortezomib selectively binds and inhibits the 20S proteasome enzyme's active sites. This study was conducted to determine the side effects and maximum tolerated dose (MTD) of bortezomib in patients with recurrent malignant glioma. Separate dose escalations were conducted in patients taking or not taking enzyme-inducing anti-seizure drugs (+/-EIASD). The starting dose in both groups was 0.9 mg/m(2) intravenously twice weekly for the first three of each 4 week cycle. Imaging assessment of response was carried out and Plasma 20S proteasome activity inhibition and imaging was conducted to monitor efficacy. The 66 patients enrolled had a median age of 51 years, median KPS of 90%, and 77% had glioblastoma multiforme. The MTD in the -EIASD group was 1.70 mg/m(2) based on grade 3 thrombocytopenia, sensory neuropathy and fatigue. In the +EIASD group escalation was terminated at 2.5 mg/m(2) without meeting meet the MTD criteria. However, proteasome inhibition in this group did not change at doses above 1.90 mg/m(2) suggesting that further escalations would be unlikely to increase a biologic effect. Mean proteasome inhibition plateaued in +EIASD patients receiving 2.1 mg/m(2) of bortezomib at 77 ± 12% and in -EIASD patients treated with a dose of 1.7 mg/m(2) at 79 ± 6%. Two partial responses were observed. This study determined that EIASDs effect the MTD of bortezomib and the dose required for maximal inhibition of whole blood 20S proteasome. Some evidence of clinical activity was noted in this phase I study in patients with recurrent high grade gliomas.
    Journal of Neuro-Oncology 03/2010; 100(1):95-103. · 3.12 Impact Factor
  • Annals of Oncology. 01/2010; 21:4-4.
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    ABSTRACT: Classical immunotherapeutic approaches to glioblastoma multiforme (GBM) have shown mixed results, and therapies focused on innate lymphocyte activity against GBM have not been rigorously evaluated. We examined peripheral blood lymphocyte phenotype, gammadelta T-cell number, mitogenic response, and cytotoxicity against GBM cell lines and primary tumor explants from GBM patients at selected time points prior to and during GBM therapy. Healthy volunteers served as controls and were grouped by age. T-cell infiltration of tumors from these patients was assessed by staining for CD3 and T-cell receptor gammadelta. Our findings revealed no differences in counts of mean absolute T-cells, T-cell subsets CD3+CD4+ and CD3+CD8+, and natural killer cells from healthy volunteers and patients prior to and immediately after GBM resection. In contrast, gammadelta T-cell counts and mitogen-stimulated proliferative response of gammadelta T-cells were markedly decreased prior to GBM resection and throughout therapy. Expanded/activated gammadelta T-cells from both patients and healthy volunteers kill GBM cell lines D54, U373, and U251, as well as primary GBM, without cytotoxicity to primary astrocyte cultures. Perivascular T-cell accumulation was noted in paraffin sections, but no organized T-cell invasion of the tumor parenchyma was seen. Taken together, these data suggest that gammadelta T-cell depletion and impaired function occur prior to or concurrent with the growth of the tumor. The significant cytotoxicity of expanded/activated gammadelta T-cells from both healthy controls and selected patients against primary GBM explants may open a previously unexplored approach to cellular immunotherapy of GBM.
    Neuro-Oncology 03/2009; 11(4):357-67. · 6.18 Impact Factor
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    ABSTRACT: Cilengitide, an inhibitor of alphavbeta3 and alphavbeta5 integrin receptors, demonstrated minimal toxicity and durable activity across a wide range of doses administered to adults with recurrent glioblastoma multiforme (GBM) in a prior phase I study. The current multicenter phase II study was conducted to evaluate the activity and safety of cilengitide in GBM patients at first recurrence. Eligible patients were randomly assigned to receive either 500 or 2,000 mg of cilengitide twice weekly on a continuous basis. Patients were assessed every 4 weeks. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included PFS, overall survival (OS), and radiographic response, as well as quality-of-life and pharmacokinetic assessments. Eighty-one patients were enrolled, including 41 on the 500-mg arm and 40 on the 2,000-mg arm. The safety profile of cilengitide was excellent, with no significant reproducible toxicities observed on either arm. Antitumor activity was observed in both treatment cohorts but trended more favorably among patients treated with 2,000 mg, including a 6-month PFS of 15% and a median OS of 9.9 months. Cilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients. Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted.
    Journal of Clinical Oncology 12/2008; 26(34):5610-7. · 18.04 Impact Factor
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    ABSTRACT: Glioblastoma multiforme (GBM), a highly invasive and vascular cancer, responds poorly to conventional cytotoxic therapy. Integrins, widely expressed in GBM and tumor vasculature, mediate cell survival, migration and angiogenesis. Cilengitide is a potent alphavbeta3 and alphavbeta5 integrin inhibitor. To summarize the preclinical and clinical experience with cilengitide for GBM. Preclinical studies and clinical trials evaluating cilengitide for GBM were reviewed. Cilengitide is active and synergizes with external beam radiotherapy in preclinical GBM models. In clinical trials for recurrent GBM, single-agent cilengitide has antitumor benefits and minimal toxicity. Among newly diagnosed GBM patients, single-arm studies incorporating cilengitide into standard external beam radiotherapy/temozolomide have shown encouraging activity with no increased toxicity and have led to a planned randomized Phase III trial.
    Expert Opinion on Investigational Drugs 09/2008; 17(8):1225-35. · 4.74 Impact Factor

Publication Stats

1k Citations
96 Downloads
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214.82 Total Impact Points

Institutions

  • 2005–2013
    • University of Alabama at Birmingham
      • • Department of Neurology
      • • Department of Neurobiology
      Birmingham, AL, United States
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
  • 2006
    • Mayo Clinic - Rochester
      • Department of Neurology
      Rochester, Minnesota, United States